{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T03:05:42Z","timestamp":1776135942201,"version":"3.50.1"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T00:00:00Z","timestamp":1664496000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["852201"],"award-info":[{"award-number":["852201"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Spanish Ministry of Economy, Industry and Competitiveness"},{"name":"Centro de Excelencia Severo Ochoa","award":["CEX2020-001049-S, MCIN\/AEI \/10.13039\/501100011033"],"award-info":[{"award-number":["CEX2020-001049-S, MCIN\/AEI \/10.13039\/501100011033"]}]},{"name":"CERCA Programme\/Generalitat de Catalunya"},{"name":"MEIC Excelencia","award":["BFU2017-88615-P"],"award-info":[{"award-number":["BFU2017-88615-P"]}]},{"DOI":"10.13039\/100001642","name":"Glenn Foundation for Medical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001642","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Aging involves a transition from youthful vigor to geriatric infirmity and death. Individuals who remain vigorous longer tend to live longer, and within isogenic populations of\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>elegan<\/jats:italic>\n                    s the timing of age-associated vigorous movement cessation (VMC) is highly correlated with lifespan. Yet, many mutations and interventions in aging alter the proportion of lifespan spent moving vigorously, appearing to \u201cuncouple\u201d youthful vigor from lifespan. To clarify the relationship between vigorous movement cessation, death, and the physical declines that determine their timing, we developed a new version of the imaging platform called \u201cThe Lifespan Machine\u201d. This technology allows us to compare behavioral aging and lifespan at an unprecedented scale. We find that behavioral aging involves a time-dependent increase in the risk of VMC, reminiscent of the risk of death. Furthermore, we find that VMC times are inversely correlated with remaining lifespan across a wide range of genotypes and environmental conditions. Measuring and modelling a variety of lifespan-altering interventions including a new RNA-polymerase II auxin-inducible degron system, we find that vigorous movement and lifespan are best described as emerging from the interplay between at least two distinct physical declines whose rates co-vary between individuals. In this way, we highlight a crucial limitation of predictors of lifespan like VMC\u2014in organisms experiencing multiple, distinct, age-associated physical declines, correlations between mid-life biomarkers and late-life outcomes can arise from the contextual influence of confounding factors rather than a reporting by the biomarker of a robustly predictive biological age.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1010415","type":"journal-article","created":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T13:58:52Z","timestamp":1664546332000},"page":"e1010415","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["A hierarchical process model links behavioral aging and lifespan in C. elegans"],"prefix":"10.1371","volume":"18","author":[{"given":"Natasha","family":"Oswal","sequence":"first","affiliation":[]},{"given":"Olivier M. F.","family":"Martin","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5489-501X","authenticated-orcid":true,"given":"Sofia","family":"Stroustrup","sequence":"additional","affiliation":[]},{"given":"Monika Anna Matusiak","family":"Bruckner","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9530-7301","authenticated-orcid":true,"given":"Nicholas","family":"Stroustrup","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,9,30]]},"reference":[{"key":"pcbi.1010415.ref001","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1534\/genetics.118.301613","article-title":"Estimates of the Heritability of Human Longevity Are Substantially Inflated due to Assortative Mating","volume":"210","author":"JG Ruby","year":"2018","journal-title":"Genetics"},{"key":"pcbi.1010415.ref002","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.cels.2016.09.003","article-title":"Extended twilight among isogenic C. elegans causes a disproportionate scaling between lifespan and health","volume":"3","author":"WB Zhang","year":"2016","journal-title":"Cell Syst"},{"key":"pcbi.1010415.ref003","doi-asserted-by":"crossref","first-page":"573","DOI":"10.18632\/aging.101414","article-title":"An epigenetic biomarker of aging for lifespan and healthspan.","volume":"10","author":"ME Levine","year":"2018","journal-title":"Aging"},{"key":"pcbi.1010415.ref004","doi-asserted-by":"crossref","first-page":"8084","DOI":"10.1073\/pnas.0400848101","article-title":"Measurements of age-related changes of physiological processes that predict lifespan of Caenorhabditis elegans","volume":"101","author":"C Huang","year":"2004","journal-title":"Proc Natl Acad Sci"},{"key":"pcbi.1010415.ref005","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.mad.2004.03.003","article-title":"Body weight, hormones and T cell subsets as predictors of life span in genetically heterogeneous mice","volume":"125","author":"JM Harper","year":"2004","journal-title":"Mech Ageing Dev"},{"key":"pcbi.1010415.ref006","doi-asserted-by":"crossref","first-page":"e72664","DOI":"10.7554\/eLife.72664","article-title":"Automated, high-dimensional evaluation of physiological aging and resilience in outbred mice.","volume":"11","author":"Z Chen","year":"2022","journal-title":"eLife"},{"key":"pcbi.1010415.ref007","doi-asserted-by":"crossref","first-page":"e1008002","DOI":"10.1371\/journal.pcbi.1008002","article-title":"Multidimensional phenotyping predicts lifespan and quantifies health in Caenorhabditis elegans.","volume":"16","author":"CN Martineau","year":"2020","journal-title":"PLOS Comput Biol"},{"key":"pcbi.1010415.ref008","doi-asserted-by":"crossref","first-page":"E4104","DOI":"10.1073\/pnas.1506264112","article-title":"Quantification of biological aging in young adults","volume":"112","author":"DW Belsky","year":"2015","journal-title":"Proc Natl Acad Sci"},{"key":"pcbi.1010415.ref009","doi-asserted-by":"crossref","first-page":"15383","DOI":"10.1073\/pnas.261228098","article-title":"Explaining mortality rate plateaus","volume":"98","author":"J Weitz","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"pcbi.1010415.ref010","doi-asserted-by":"crossref","DOI":"10.1007\/978-0-387-68560-1","volume-title":"Survival and Event History Analysis : A Process Point of View.","author":"O Aalen","year":"2008"},{"key":"pcbi.1010415.ref011","doi-asserted-by":"crossref","first-page":"e13320","DOI":"10.1111\/acel.13320","article-title":"BiT age: A transcriptome-based aging clock near the theoretical limit of accuracy","volume":"20","author":"DH Meyer","year":"2021","journal-title":"Aging Cell"},{"key":"pcbi.1010415.ref012","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1186\/s13059-019-1824-y","article-title":"DNA methylation aging clocks: challenges and recommendations","volume":"20","author":"CG Bell","year":"2019","journal-title":"Genome Biol"},{"key":"pcbi.1010415.ref013","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1038\/s41591-019-0673-2","article-title":"Undulating changes in human plasma proteome profiles across the lifespan","volume":"25","author":"B Lehallier","year":"2019","journal-title":"Nat Med"},{"key":"pcbi.1010415.ref014","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.18632\/aging.101842","article-title":"Age-dependent co-dependency structure of biomarkers in the general population of the United States","volume":"11","author":"AL Goallec","year":"2019","journal-title":"Aging"},{"key":"pcbi.1010415.ref015","doi-asserted-by":"crossref","first-page":"e51507","DOI":"10.7554\/eLife.51507","article-title":"Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up.","volume":"9","author":"X Li","year":"2020","journal-title":"eLife"},{"key":"pcbi.1010415.ref016","doi-asserted-by":"crossref","first-page":"e1000450","DOI":"10.1371\/journal.pbio.1000450","article-title":"Widespread protein aggregation as an inherent part of aging in C. elegans","volume":"8","author":"DC David","year":"2010","journal-title":"PLoS Biol"},{"key":"pcbi.1010415.ref017","doi-asserted-by":"crossref","first-page":"8919","DOI":"10.1038\/ncomms9919","article-title":"C. elegans maximum velocity correlates with healthspan and is maintained in worms with an insulin receptor mutation","volume":"6","author":"J-H Hahm","year":"2015","journal-title":"Nat Commun"},{"key":"pcbi.1010415.ref018","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1038\/nature01135","article-title":"Stochastic and genetic factors influence tissue-specific decline in ageing \\emphCaenorhabditis elegans","volume":"419","author":"LA Herndon","year":"2002","journal-title":"Nature"},{"key":"pcbi.1010415.ref019","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.conb.2015.03.009","article-title":"C. elegans locomotion: small circuits, complex functions","volume":"33","author":"M Zhen","year":"2015","journal-title":"Curr Opin Neurobiol"},{"key":"pcbi.1010415.ref020","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1113\/JP270561","article-title":"Innervation and neuromuscular control in ageing skeletal muscle","volume":"594","author":"RT Hepple","year":"2016","journal-title":"J Physiol"},{"key":"pcbi.1010415.ref021","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1093\/gerona\/glp033","article-title":"Quantitative Gait Markers and Incident Fall Risk in Older Adults","volume":"64A","author":"J Verghese","year":"2009","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"pcbi.1010415.ref022","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1093\/genetics\/161.3.1101","article-title":"Genetic analysis of tissue aging in \\emphCaenorhabditis elegans: a role for heat-shock factor and bacterial proliferation","volume":"161","author":"D Garigan","year":"2002","journal-title":"Genetics"},{"key":"pcbi.1010415.ref023","doi-asserted-by":"crossref","first-page":"E277","DOI":"10.1073\/pnas.1412192112","article-title":"Uncoupling lifespan and healthspan in \\emphCaenorhabditis elegans longevity mutants","volume":"112","author":"A Bansal","year":"2015","journal-title":"Proc Natl Acad Sci"},{"key":"pcbi.1010415.ref024","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.celrep.2017.03.062","article-title":"How a Mutation that Slows Aging Can Also Disproportionately Extend End-of-Life Decrepitude","volume":"19","author":"K Podshivalova","year":"2017","journal-title":"Cell Rep"},{"key":"pcbi.1010415.ref025","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1111\/j.1474-9726.2010.00571.x","article-title":"Two modes of mitochondrial dysfunction lead independently to lifespan extension in \\emphCaenorhabditis elegans","volume":"9","author":"W Yang","year":"2010","journal-title":"Aging Cell"},{"key":"pcbi.1010415.ref026","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1093\/emboj\/18.7.1783","article-title":"CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans","volume":"18","author":"S Felkai","year":"1999","journal-title":"EMBO J"},{"key":"pcbi.1010415.ref027","doi-asserted-by":"crossref","first-page":"e26652","DOI":"10.7554\/eLife.26652","article-title":"Longitudinal imaging of Caenorhabditis elegans in a microfabricated device reveals variation in behavioral decline during aging.","volume":"6","author":"MA Churgin","year":"2017","journal-title":"eLife"},{"key":"pcbi.1010415.ref028","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nmeth.2475","article-title":"The Caenorhabditis elegans Lifespan Machine.","volume":"10","author":"N Stroustrup","year":"2013","journal-title":"Nat Methods"},{"key":"pcbi.1010415.ref029","doi-asserted-by":"crossref","first-page":"2730","DOI":"10.1016\/j.celrep.2018.02.050","article-title":"Coupling of Rigor Mortis and Intestinal Necrosis during C. elegans Organismal Death","volume":"22","author":"ER Galimov","year":"2018","journal-title":"Cell Rep"},{"key":"pcbi.1010415.ref030","doi-asserted-by":"crossref","first-page":"B331","DOI":"10.1093\/gerona\/56.8.B331","article-title":"Age-specific demographic profiles of longevity mutants in Caenorhabditis elegans show segmental effects","volume":"56","author":"TE Johnson","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"pcbi.1010415.ref031","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1126\/science.1086016","article-title":"Demography of dietary restriction and death in Drosophila","volume":"301","author":"W Mair","year":"2003","journal-title":"Science"},{"key":"pcbi.1010415.ref032","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1126\/science.8503016","article-title":"Compositional interpretations of medfly mortality","volume":"260","author":"JW Vaupel","year":"1993","journal-title":"Science"},{"key":"pcbi.1010415.ref033","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nature16550","article-title":"The temporal scaling of Caenorhabditis elegans ageing","volume":"530","author":"N Stroustrup","year":"2016","journal-title":"Nature"},{"key":"pcbi.1010415.ref034","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1126\/science.aat3119","article-title":"The plateau of human mortality: Demography of longevity pioneers","volume":"360","author":"E Barbi","year":"2018","journal-title":"Science"},{"key":"pcbi.1010415.ref035","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1177\/096228029400300303","article-title":"Effects of frailty in survival analysis.","volume":"3","author":"O. Aalen","year":"1994","journal-title":"Stat Methods Med Res"},{"key":"pcbi.1010415.ref036","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1177\/0962280208092301","article-title":"Multi-state models for the analysis of time-to-event data.","volume":"18","author":"L Meira-Machado","year":"2009","journal-title":"Stat Methods Med Res"},{"key":"pcbi.1010415.ref037","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1126\/science.1077780","article-title":"Rates of Behavior and Aging Specified by Mitochondrial Function During Development","volume":"2398","author":"A. Dillin","year":"2002","journal-title":"Science"},{"key":"pcbi.1010415.ref038","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1093\/genetics\/141.3.977","article-title":"Identification and cloning of unc-119, a gene expressed in the Caenorhabditis elegans nervous system","volume":"141","author":"M Maduro","year":"1995","journal-title":"Genetics"},{"key":"pcbi.1010415.ref039","doi-asserted-by":"crossref","first-page":"13091","DOI":"10.1073\/pnas.95.22.13091","article-title":"The genetics of caloric restriction in Caenorhabditis elegans","volume":"95","author":"B Lakowski","year":"1998","journal-title":"Proc Natl Acad Sci"},{"key":"pcbi.1010415.ref040","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2006.01.039","article-title":"Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling","volume":"124","author":"JR Berman","year":"2006","journal-title":"Cell"},{"key":"pcbi.1010415.ref041","doi-asserted-by":"crossref","first-page":"8359","DOI":"10.1038\/s41598-018-26552-9","article-title":"Swimming Exercise and Transient Food Deprivation in Caenorhabditis elegans Promote Mitochondrial Maintenance and Protect Against Chemical-Induced Mitotoxicity.","volume":"8","author":"JH Hartman","year":"2018","journal-title":"Sci Rep."},{"key":"pcbi.1010415.ref042","first-page":"1850","article-title":"Effects of exercise on longevity of rats","volume":"46","author":"JO Holloszy","year":"1987","journal-title":"Fed Proc"},{"key":"pcbi.1010415.ref043","doi-asserted-by":"crossref","first-page":"l2323","DOI":"10.1136\/bmj.l2323","article-title":"Physical activity trajectories and mortality: population based cohort study","volume":"365","author":"A Mok","year":"2019","journal-title":"BMJ"},{"key":"pcbi.1010415.ref044","doi-asserted-by":"crossref","first-page":"5495","DOI":"10.1038\/s41467-019-13192-4","article-title":"Senescent cell turnover slows with age providing an explanation for the Gompertz law","volume":"10","author":"O Karin","year":"2019","journal-title":"Nat Commun"},{"key":"pcbi.1010415.ref045","first-page":"4374","article-title":"The auxin-inducible degradation (AID) system enables versatile conditional protein depletion in C.","volume":"142","author":"L Zhang","year":"2015","journal-title":"Dev Camb Engl"},{"key":"pcbi.1010415.ref046","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1534\/genetics.119.301965","article-title":"Efficient Generation of Endogenous Fluorescent Reporters by Nested CRISPR in Caenorhabditis elegans","volume":"211","author":"J Vicencio","year":"2019","journal-title":"Genetics"},{"key":"pcbi.1010415.ref047","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1534\/g3.119.400781","article-title":"Rapid Degradation of Caenorhabditis elegans Proteins at Single-Cell Resolution with a Synthetic Auxin","volume":"10","author":"MAQ Martinez","year":"2020","journal-title":"G3 Bethesda Md."},{"key":"pcbi.1010415.ref048","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1093\/ije\/dyu192","article-title":"Understanding variation in disease risk: the elusive concept of frailty.","volume":"44","author":"OO Aalen","year":"2015","journal-title":"Int J Epidemiol"},{"key":"pcbi.1010415.ref049","first-page":"e65026","article-title":"Global, cell non-autonomous gene regulation drives individual lifespan among isogenic","volume":"10","author":"HE Kinser","year":"2021","journal-title":"C. elegans. Gruber JeLife"},{"key":"pcbi.1010415.ref050","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s10522-009-9228-0","article-title":"Modulation of aging profiles in isogenic populations of Caenorhabditis elegans by bacteria causing different extrinsic mortality rates.","volume":"11","author":"S Baeriswyl","year":"2010","journal-title":"Biogerontology"},{"key":"pcbi.1010415.ref051","doi-asserted-by":"crossref","first-page":"439","DOI":"10.2307\/2061224","article-title":"The impact of heterogeneity in individual frailty on the dynamics of mortality.","volume":"16","author":"JW Vaupel","year":"1979","journal-title":"Demography"},{"key":"pcbi.1010415.ref052","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v070.i08","article-title":"flexsurv: A Platform for Parametric Survival Modeling in R","volume":"70","author":"C. Jackson","year":"2016","journal-title":"J Stat Softw"},{"key":"pcbi.1010415.ref053","unstructured":"Harrell, Frank E Jr. rms: Regression Modeling Strategies. 2022. Available: https:\/\/CRAN.R-project.org\/package=rms."},{"key":"pcbi.1010415.ref054","unstructured":"Zhang D. rsq: R-Squared and Related Measures. 2022. Available: https:\/\/CRAN.R-project.org\/package=rsq."}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010415","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T13:59:54Z","timestamp":1664546394000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010415"}},"subtitle":[],"editor":[{"given":"Adriana","family":"San Miguel","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,9,30]]},"references-count":54,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010415","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.03.31.437415","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,30]]}}}